Programming of hepatic lipid metabolism in a rat model of postnatal nicotine exposure – Sex-related differences

Bertasso, Iala Milene; Pietrobon, Carla Bruna; Lopes, Bruna Pereira; Peixoto, Thamara Cherem; Soares, P.N.; Oliveira, Elaine de; Manhães, Alex C.; Bonfleur, Maria Lúcia; Balbo, Sandra Lucinei; Cabral, S.S.; Kluck, George Eduardo Gabriel; Atella, Geórgia C.; Moura, Egberto Gaspar de; Lisboa, Patrícia Cristina

doi:10.1016/j.envpol.2019.113781

Cited by 7 publications

(22 citation statements)

References 67 publications

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“…23 Our present study showed that MNE induced serum lipid accumulation and caused liver alterations consistent with MAFLD, and these findings are supported by previous reports. [18][19][20]24 Moreover, MNE promoted diet-induced serum lipid accumulation and elevated serum ALT and AST levels.…”

Section: Discussionmentioning

confidence: 97%

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Huang

Chen

et al. 2021

Liver International

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Aim The aim of this study is to investigate the effect of maternal nicotine exposure (MNE) on the development of metabolic associated fatty liver disease (MAFLD) in adulthood offspring and the underlying mechanism. Methods Pregnant mice (n = 22) were subcutaneously injected with either saline vehicle (n = 11) or nicotine (n = 11) twice a day on gestational days 11‐21. Offspring mice (n = 176) from both groups were weaned at postnatal day 21, and for 6 months after postnatal day 21, 96 mice were fed either a standard chow diet (n = 48) or a high‐fat diet (n = 48). Serum lipid indicators, liver function indicators, insulin, and liver mitochondrial respiration were analyzed. The expression levels of fibrosis‐related proteins, phosphorylated PI3K, phosphorylated Akt, sterol regulatory element‐binding transcription factor 1 (SREBP1c), and peroxisome proliferator‐activated receptor alpha (PPAR‐α) were detected in the liver by immunohistochemistry and Western blotting. Results MNE significantly decreased the weight of both maternal and offspring mice (~30%) and inhibited organ growth in offspring mice (P < .05). MNE also significantly increased serum levels of total bile acid, triglycerides, total cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, low‐density lipoprotein, and insulin while decreasing serum high‐density lipoprotein levels and mitochondrial respiration activity in mice fed either the normal diet or high‐fat diet (all P < .05). These effects of MNE on lipid metabolism and insulin resistance were mediated via PI3K and Akt phosphorylation and down‐regulation of SREBP1c and PPAR‐α. Conclusion Our data indicate MNE induces lipid metabolism disorder and insulin resistance to promote MAFLD progression in adult offspring through activation of PI3K/Akt signaling and suppression of SREBP1c and PPARα protein expression.

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Section: Discussionmentioning

confidence: 97%

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Huang

Chen

et al. 2021

Liver International

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“…In contrast, NIC females had a reduction of DAGL and CB1 receptor in the liver, which may help to protect this tissue from the harmful effects of ECS overstimulation, since NIC females have unchanged hepatic cytoarchitecture, as we have previously shown. 52 It is possible that a compensatory effect is improving liver function by a mechanism remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Nicotine exposure during breastfeeding alters the expression of endocannabinoid system biomarkers in female but not in male offspring at adulthood

Miranda

Rodrigues

Peixoto

et al. 2023

J Dev Orig Health Dis

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Early nicotine exposure compromises offspring’s phenotype at long-term in both sexes. We hypothesize that offspring exposed to nicotine during breastfeeding show deregulated central and peripheral endocannabinoid system (ECS), compromising several aspects of their metabolism. Lactating rats received nicotine (NIC, 6 mg/Kg/day) or saline from postnatal day (PND) 2 to 16 through implanted osmotic minipumps. Offspring were analyzed at PND180. We evaluated protein expression of N-acylphosphatidylethanolamide-phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DAGL), monoacylglycerol lipase (MAGL) and cannabinoid receptors (CB1 and/or CB2) in lateral hypothalamus, paraventricular nucleus of the hypothalamus, liver, visceral adipose tissue (VAT), adrenal and thyroid. NIC offspring from both sexes did not show differences in hypothalamic ECS markers. Peripheral ECS markers showed no alterations in NIC males. In contrast, NIC females had lower liver DAGL and CB1, higher VAT DAGL, higher adrenal NAPE-PLD and higher thyroid FAAH. Endocannabinoids biosynthesis was affected by nicotine exposure during breastfeeding only in females; alterations in peripheral tissues suggest lower action in liver and higher action in VAT, adrenal and thyroid. Effects of nicotine exposure during lactation on ECS markers are sex- and tissue-dependent. This characterization helps understanding the phenotype of the adult offspring in this model and may contribute to the development of new pharmacological targets for the treatment of several metabolic diseases that originate during development.

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“…29 NIC females only showed higher serum TGs. 29 We used the samples of this previously published model 41 and investigated the molecular mechanism of this sexual dimorphism in the liver. As shown in Fig.…”

Section: Resultsmentioning

confidence: 85%

“…Male offspring exposed to nicotine early in adulthood exhibited increased liver markers of oxidative stress, de novo lipogenesis, and increased hepatic triglyceride (TG) levels (steatosis) in the presence of normal plasma lipids. 28,29 In early exposed females, despite normal hepatic morphology and TG content, these subjects showed paradoxically higher protein expression of ACC-1 and FAS (acetyl-CoA carboxylase-1 and fatty acid synthase, respectively) in the liver, as well as higher cholesterol and TG in plasma. 29 It is well established that the liver plays a pivotal role in controlling lipid metabolism and that changes in the pathways involved in hepatic homeostasis, such as ER stress and autophagy, could contribute to the sexual dimorphism phenotype observed in this model.…”

Section: Introductionmentioning

confidence: 99%

“…28,29 In early exposed females, despite normal hepatic morphology and TG content, these subjects showed paradoxically higher protein expression of ACC-1 and FAS (acetyl-CoA carboxylase-1 and fatty acid synthase, respectively) in the liver, as well as higher cholesterol and TG in plasma. 29 It is well established that the liver plays a pivotal role in controlling lipid metabolism and that changes in the pathways involved in hepatic homeostasis, such as ER stress and autophagy, could contribute to the sexual dimorphism phenotype observed in this model. Increased hepatic lipogenesis can induce oxidative and ER stress based on offspring susceptibility.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal nicotine exposure affects adult rat hepatic pathways involved in endoplasmic reticulum stress and macroautophagy in a sex-dependent manner

Souza,

Rossetti,

Peixoto

et al. 2023

J Dev Orig Health Dis

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Nonalcoholic fatty liver disease (NAFLD) involves changes in hepatic pathways, as lipogenesis, oxidative stress, endoplasmic reticulum (ER) stress, and macroautophagy. Maternal nicotine exposure exclusively during lactation leads to fatty liver (steatosis) only in the adult male offspring, not in females. Therefore, our hypothesis is that neonatal exposure to nicotine sex-dependently affects the signaling pathways involved in hepatic homeostasis of the offspring, explaining the hepatic lipid accumulation phenotype only in males. For this, between postnatal days 2 and 16, Wistar rat dams were implanted with osmotic minipumps, which released nicotine (NIC; 6 mg/Kg/day) or vehicle. The livers of offspring were evaluated at postnatal day 180. Only the male offspring that had been exposed to nicotine neonatally showed increased protein expression of markers of unfolded protein response (UPR), highlighting the presence of ER stress, as well as disruption of the activation of the macroautophagy repair pathway. These animals also had increased expression of diacylglycerol O-acyltransferase 1 and 4-hydroxynonenal, suggesting increased triglyceride esterification and oxidative stress. These parameters were not altered in the female offspring that had been neonatally exposed to nicotine, however they exhibited increased phospho adenosine monophosphate-activated protein kinase pAMPK expression, possibly as a protective mechanism. Thus, the disturbance in the hepatic homeostasis by UPR, macroautophagy, and oxidative stress modifications seem to be the molecular mechanisms underlying the liver steatosis in the adult male offspring of the nicotine-programming model. This highlights the importance of maternal smoking cessation during breastfeeding to decrease the risk of NAFLD development, especially in males.

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Programming of hepatic lipid metabolism in a rat model of postnatal nicotine exposure – Sex-related differences

Cited by 7 publications

References 67 publications

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Nicotine exposure during breastfeeding alters the expression of endocannabinoid system biomarkers in female but not in male offspring at adulthood

Neonatal nicotine exposure affects adult rat hepatic pathways involved in endoplasmic reticulum stress and macroautophagy in a sex-dependent manner

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